Method for Preparing Key Intermediate of ABT-737 and Method for Preparing ABT-737

Abstract

The present disclosure relates to the technical field of drug synthesis, and provides a method for preparing a key intermediate of ABT-737 and a method for preparing ABT-737. In the present disclosure, the compound having a structure represented by formula I is used as the starting material. The carboxyl group in the compound having a structure represented by formula I is first reduced to a hydroxyl group, followed by a vulcanization by a vulcanizing agent, and then an amination, a deprotection, a condensation, and a carbonyl group reduction, to obtain the key intermediate of ABT-737 having a structure represented by formula VI. Tert-butoxycarbonyl is used as the protecting group for the compound having a structure represented by formula I, and the subsequent intermediate containing the protecting group of tert-butoxycarbonyl is stable, and easy to be deprotected. This method is suitable for mass synthesis, with high product yield and low production cost, and thus has a good industrialization prospect.

1 . A method for preparing a key intermediate of ABT-737, comprising
 (1) subjecting a compound having a structure represented by formula I and an activator to an esterification reaction to obtain an active ester, subjecting the active ester and a first reducing agent to a reduction reaction to obtain a compound having a structure represented by formula II,   
       
         
           
           
               
               
           
         
         (2) subjecting the compound having a structure represented by formula II, a vulcanizing agent, and an organic phosphine to a vulcanization reaction to obtain a compound having a structure represented by formula III, wherein the vulcanizing agent comprises one or more selected from the group consisting of a thiophenol metal salt and diphenyl disulfide, 
       
       
         
           
           
               
               
           
         
       
       in formula I to formula III, R represents a chain alkyl group or cycloalkyl group;
 (3) subjecting the compound having a structure represented by formula III to a hydrolysis reaction under an alkaline condition to obtain a hydrolysate, and subjecting the hydrolysate and dimethylamine to an amination reaction to obtain a compound having a structure represented by formula IV, 
 
       
         
           
           
               
               
           
         
         (4) subjecting the compound having a structure represented by formula IV to a deprotection reaction with a deprotection reagent to obtain a deprotected product, and subjecting the deprotected product to a condensation reaction with 3-nitro-4-halobenzenesulfonamide to obtain a compound having a structure represented by formula V, 
       
       
         
           
           
               
               
           
         
       
       and
 (5) subjecting the compound having a structure represented by formula V and a second reducing agent to a carbonyl reduction reaction under an acidic condition to obtain the key intermediate of ABT-737 having a structure represented by formula VI, 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method as claimed in  claim 1 , wherein the activator includes N-hydroxysuccinimide, isobutyl chloroformate, or a combination thereof; a molar ratio of the compound having a structure represented by formula Ito the activator is in the range of 1:(1-1.2);
 the esterification reaction is conducted at a temperature of −20° C. to 0° C. for 20-25 h.   
     
     
         3 . The method as claimed in claim wherein the esterification reaction is carried out under the catalysis of a catalyst, and the catalyst is an organic amine;
 a molar ratio of the compound having a structure represented by formula I to the catalyst is in the range of 1:(1.05-1.5).   
     
     
         4 . The method as claimed in  claim 1 , wherein in step (1), the first reducing agent is a boron reducing agent; a molar ratio of the active ester to the first reducing agent is in the range of 1:(1.5-2);
 the reduction reaction is carried out in a mixed solvent, and the mixed solvent comprises one or more selected from the group consisting of a tetrahydrofuran-water mixed solvent, a tetrahydrofuran-methanol mixed solvent, and a methanol-water mixed solvent;   the reduction reaction is conducted at a temperature of −5° C. to 20° C. for 5-20 min.   
     
     
         5 . The method as claimed in  claim 1 , wherein a molar ratio of the compound having a structure represented by formula II to the vulcanizing agent is in the range of 1:(1.2-2);
 the organic phosphine comprises one or more selected from the group consisting of tributyl phosphine, triphenyl phosphine, and tricarboxyethyl phosphine; a molar ratio of the compound having a structure represented by formula II to the organic phosphine is in the range of 1:(1.2-2);   the vulcanization reaction is conducted at a temperature of 70-85° C. for 15-20 h.   
     
     
         6 . The method as claimed in  claim 1 , wherein in step (3), the alkaline condition is provided by an inorganic base;
 a molar ratio of the compound having a structure represented by formula III to the inorganic base is in the range of 1:(2-4);   the hydrolysis reaction is conducted at room temperature for 20-24 h.   
     
     
         7 . The method as claimed in  claim 1 , wherein the amination reaction is carried out under the conditions of a condensing agent and a catalyst, wherein the condensing agent comprises dicyclohexylcarbodiimide, 3-(ethyliminomethylideneamino)-N,N-dimethylpropan-1-amine hydrochloride, or a combination thereof, and the catalyst comprises 4-dimethylaminopyridine, N,N-diisopropylethylamine, or a combination thereof;
 a molar ratio of the hydrolysate, the condensing agent, and the catalyst is in the range of 1:(1.8-2.5) :(2-2.2);   a molar ratio of the hydrolysate to dimethylamine is in the range of 1:(1.5-2.5);   the amination reaction is conducted at room temperature for 20-30 h.   
     
     
         8 . The method as claimed in  claim 1 , wherein the deprotection reagent is one or more selected from the group consisting of aqueous hydrochloric acid solution, hydrogen chloride-methanol solution, hydrogen chloride-ethyl acetate solution, and trifluoroacetic acid;
 the deprotection reaction is conducted at room temperature for 2-5 h.   
     
     
         9 . The method as claimed in  claim 1 , wherein a molar ratio of the deprotected product to 3-nitro-4-halobenzenesulfonamide is in the range of 1:(1.05-1.3);
 the condensation reaction is conducted at a temperature of 20-30° C. for 20-30 h.   
     
     
         10 . The method as claimed in  claim 1 , wherein in step (5), the second reducing agent is a boron reducing agent; the acidic condition is provided by an acidic reagent, and the acidic reagent comprises hydrochloric acid, trifluoroacetic acid, or a combination thereof;
 the carbonyl reduction reaction is conducted specifically as follows:mixing a compound having a structure represented by formula V and a boron reducing agent, and subjecting the resulting mixture to a complexation reaction to obtain a boron complex; mixing the boron complex and an acidic reagent, and subjecting the resulting mixture to a hydrolysis reaction to obtain the compound having a structure represented by formula VI.   
     
     
         11 . The method as claimed in  claim 1 , wherein step (4) is replaced by step (4′), and step (5) is replaced by (5′):
 (4′) under the actions of the second reducing agent and the acidic reagent, subjecting the compound having a structure represented by formula IV to a carbonyl reduction reaction to obtain a compound having a structure represented by formula V′, 
 
       
         
           
           
               
               
           
         
       
       and
 (5′) under the action of the deprotection reagent, subjecting the compound having a structure represented by formula V to a deprotection reaction to obtain a deprotected product, and subjecting the deprotected product to a condensation reaction with 3-nitro-4-halobenzenesulfonamide to obtain the key intermediate of ABT-737. 
 
     
     
         12 . A method for preparing ABT-737, comprising preparing the key intermediate of ABT-737 according to the method of  claim 1 ; and
 mixing the key intermediate of ABT-737 with 4-(4-((4′-chloro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl) benzoic acid, and subjecting the mixture to a condensation reaction to obtain ABT-737 having a structure represented by formula VII,   
       
         
           
           
               
               
           
         
       
     
     
         13 . The method as claimed in  claim 12 , wherein a molar ratio of the key intermediate of ABT-737 to 4-(4-((4′-chloro-[1,1′-biphenyl]-2-yl) methyl piperazin-1-yl) benzoic acid is in the range of 1:(1.05-1.1). 
     
     
         14 . The method as claimed in  claim 12 , wherein the condensation reaction is carried out under the actions of a condensing agent and a catalyst, wherein the condensing agent is dicyclohexylcarbodiimide, 3-(ethyliminomethylideneamino)-N,N-dimethylpropan-1-amine hydrochloride, or a combination thereof, and the catalyst is 4-dimethylaminopyridine, N,N-diisopropylethylamine, or a combination thereof. 
     
     
         15 . The method as claimed in  claim 14 , wherein a molar ratio of the key intermediate of ABT-737, the condensing agent, and the catalyst is preferably in the range of 1:(2-2.5):(2-2.5), and more preferably 1:2.1:2.1. 
     
     
         16 . The method as claimed in  claim 12 , wherein the condensation reaction is conducted at room temperature for 40-60 h. 
     
     
         17 . The method as claimed in  claim 2 , wherein the esterification reaction is carried out under the catalysis of a catalyst, and the catalyst is an organic amine; a molar ratio of the compound having a structure represented by formula I to the catalyst is in the range of 1:(1.05-1.5).